Pseudopolymorphic forms of 2-[2-[4-[Bis (4-fluorophenyl) methyl]-1-piperazinyl]ethoxy]acetic acid dihydrochloride

ABSTRACT

The present invention relates to new pseudopolymorphic forms of 2-[2-[4-[bis (4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic acid dihydrochloride, namely, anhydrous 2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic acid dihydrochloride and 2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic acid dihydrochloride monohydrate. It also relates to processes for the preparation of these pseudopolymorphic forms and to pharmaceutical compositions containing them.

This is a divisional of Ser. No. 09/555,021, filed May 23, 2000 now U.S.Pat. No. 6,262,057.

The present invention relates to new pseudopolymorphic crystalline formsof 2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic aciddihydrochloride, to processes for their preparation and topharmaceutical compositions containing them.

2-[2-[4-[Bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic acid,also known and hereinafter referred to as efletirizine (INN:International Non-proprietary Name), is the compound of the followingformula:

Efletirizine is encompassed within general formula I of European patentNo. 58146 in the name of the applicant, which relates to substitutedbenzhydrylpiperazine derivatives.

Like 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]aceticacid, also known and hereinafter referred to as cetirizine (INN),efletirizine has been found to possess excellent antihistaminicproperties. It belongs to the pharmacological class of second generationhistamine H₁-receptor antagonists and shows in vitro high affinity andselectivity for H₁-receptors. Like cetirizine, it is useful as anantiallergic, antihistaminic, bronchodilator and antispasmodic agent.Recent clinical studies have shown the utility of efletirizine whenadministered in the form of a nasal spray for the treatment of allergicrhinitis and rhino-conjunctivitis (J. F. Dessanges et al., Allergy andClin. Immunol. News (1994), Suppl. n°2, abstract 1864; C. De Vos et al.,Allergy and Clin. Immunol. News (1994), Suppl. n°2, abstract 428).

Another recent clinical pharmacology study (to be published) has shownthat efletirizine gives unexpectedly good results in the treatment ofurticaria, atopic dermatitis and prurit.

Due to increasing therapeutic interest for efletirizine, we have set outto prepare pharmaceutical compositions containing efletirizine.

Efletirizine is an amorphous solid. However, it is highly desirable todispose of a product with reproducible characteristics, which alwaysperforms in the same way during formulation, in particular in order tocomply with regulatory requirements. For these reasons, we attempted toprepare crystalline forms of efletirizine. Although efletirizine hasbeen studied for its therapeutic utility, no attention has yet beengiven to such crystalline forms.

The present invention derives from the unexpected discovery of twopseudopolymorphic crystalline forms of efletirizine dihydrochloride,namely anhydrous efletirizine dihydrochloride and efletirizinedihydrochloride monohydrate. For the sake of identification, anhydrousefletirizine dihydrochloride will be hereinafter designated as “Form A”and efletirizine dihydrochloride monohydrate will be hereinafterdesignated as “Form B”.

According to another embodiment, the present invention provides for thepreparation of these new pseudopolymorphic forms, and further providesprocesses for the conversion of Form A into Form B and of Form B intoForm A.

The present invention also derives from the discovery that these two newpseudopolymorphic forms have different properties. In particular, wehave discovered that solid pharmaceutical compositions comprising Form Aof efletirizine dihydrochloride exhibit better storage stability overtime than solid pharmaceutical compositions comprising Form B. Thisbetter storage stability appears to be due to better compatibility withthe solid carriers and diluents commonly used in such solidpharmaceutical compositions.

Accordingly, the present invention also relates to pharmaceuticalcompositions comprising Form A or Form B in association with suitablepharmaceutical excipients, carriers or diluents therefor, preferably tosolid pharmaceutical compositions comprising Form A.

As to the preparation processes of these pseudopolymorphic forms ofefletirizine dihydrochloride, Form B may be obtained by hydrolysis in anaqueous medium of2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxyacetamide in thepresence of hydrochloric acid, at a temperature comprised between 40° C.and the reflux temperature of the reaction mixture. Form B can then berecrystallised in aqueous acid or in a mixture of solvents containingwater and hydrochloric acid.

Form B can then be transformed into Form A by heating up to reflux in asolvent, such as acetone or methylethylketone. Optionally, Form A can beconverted back into Form B by recrystallisation in aqueous hydrochloricacid.

The following examples illustrate processes for the preparation ofefletirizine dihydrochloride Form A and Form B according to the presentinvention. In these examples, differential thermograms were recorded ona PERKIN ELMER Differential Scanning Calorimeter DSC 7 with atemperature gradient of 20° C./min.

1. Preparation of2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxyacetamide and of2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxyacetamidedihydrochloride.

A suspension of 11.0 g (0.038 mol) of1-[bis(4-fluorophenyl)methyl]-piperazine, 10.5 g (0.076 mol) of2-(2-chlorethoxy)acetamide and 8.1 g of anhydrous sodium carbonate in 40ml of xylene is heated under reflux at 140° C. for 4 hours. Theprecipitate which forms is filtered off and then washed with toluene.The filtrate and toluene used for washing are combined. The resultingorganic phase is extracted with 80 ml of 1N aqueous hydrochloride acid,and the aqueous phase is washed twice with toluene. Toluene is added tothe resulting aqueous phase, then 80 ml of 1N aqueous sodium hydroxydesolution are added, and the aqueous mixture is extracted once withtoluene. The organic phase is washed once with water, dried overanhydrous sodium sulphate and the solvents are evaporated off with arotative evaporator until dryness. At this stage, the evaporationresidue consists of2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxyacetamide, whichmay be converted into its dihydrochloride salt as follows: theevaporation residue is taken up with 50 ml isopropanol and filtered; a4.38 N alcoholic hydrochloric acid solution (17.5 ml) is added to theisopropanol solution and the mixture is allowed to crystallize. Theprecipitate is filtered, washed with isopropanol and diethyl ether, thendried in vacuo. This way, 15.8 g (90%)2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxyacetamidedihydrochloride are obtained.

Melting point: 229.51° C. Mass spectrum: 389 (free base M⁺), 345 and 203

2. Preparation of Efletirizine.

In a round-bottomed flask fitted with a mechanical stirrer, a Nitrogeninlet and a condenser, 30 g (0.065 mole) of2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxyacetamidedihydrochloride are added to a mixture of 325 ml of ethanol, 130 ml of a1 N aqueous sodium hydroxyde solution and 62 ml of a 6.3 N aqueoussodium hydroxide solution. The mixture is heated under reflux and undera Nitrogen atmosphere for 1.5 hours. The reaction mixture is then cooleddown to room temperature and its pH is adjusted to 5 with 78 ml of a 5 Naqueous hydrochloric acid solution. Water is added, and ethanol isevaporated off under vacuum using a rotary evaporator. The resultingaqueous phase is extracted with dichloromethane. The organic phase isdried over anhydrous sodium sulphate and evaporated to dryness to give25 g of crude efletirizine as an amorphous solid, 5 g of which arerecrystallized in acetonitrile.

Analysis for C₂₁H₂₄F₂N₂O₃: calc. C: 64.60; H: 6.19; N: 7.17; F: 9.73.found C: 64.45; H: 6.27; N: 7.24; F: 9.44.

3. Preparation of efletirizine dihydrochloride monohydrate (Form B).

A 37% (w/w) aqueous hydrochloric acid solution (6.38 l) is added to asuspension of 2.76 kg (7.1 mole)2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxyacetamide in 6.4 lof water. The reaction mixture is heated at 65° C. for 1 hour. It isthen cooled down to about 0° C. and allowed to crystallize. Theprecipitate which forms is filtered off at 0° C., washed with HCl 6N(1.5 l), and crude efletirizine dihydrochloride monohydrate is obtained.

The crude product is then dissolved by heating at 60° C. in 13.5 l ofwater, and the solution is washed twice with 1 l toluene. The aqueousphase is then acidified with 16 l of a 37% (w/w) aqueous hydrochlorideacid solution and cooled to 0° C. The precipitate which forms isfiltered off at 0° C., washed with HCl 6N (2,4 l), and the product isdried at about 50° C. for 4 days. Efletirizine dihydrochloridemonohydrate is obtained as a white solid (yield: 3.14 kg: 92%).

The differential scanning thermogram of Form B shows a first endothermpeak between 155 and 170° C., and a second endotherm peak between 210and 235° C.

4. Preparation of anhydrous efletirizine dihydrochloride (Form A);conversion of Form B into Form A.

A suspension of 3.143 kg (6.53 mol) of Form B prepared at example 3 in35 l methylethylketone is prepared. The mixture is heated up to refluxtemperature for 2 hours. Water is removed at reflux temperature during 2hours and 50 minutes while adding progressively 5 l ofmethylethylketone. The resulting mixture is cooled to 25° C., stirredfor one night, then filtered and washed with methylethylketone (10 l).This way, anhydrous efletirizine dihydrochloride (Form A) is obtained,which is dried at 50° C. under vacuum (Yield: 98.6%, 2983 g).

Analysis for C₂₁H₂₄F₂N₂O₃.2HCl: calc. C: 54.44; H: 5.66; N: 6.05; Cl:15.30; F: 8.19. found C: 54.80; H: 5.68; N: 5.86; Cl: 15.50; F: 8.21.

The differential scanning thermogram of Form A shows an endotherm peakbetween 220 and 235° C.

5. Conversion of Form A into Form B.

A suspension of 699 g of Form A prepared at example 4 in 3 l water isprepared. The mixture is heated at 60° C. until complete dissolution andis immediately filtered. A 37% (w/w) aqueous hydrochloric acid solution(3 l) is added at 50° C. to this solution over a period of 30 min.Crystallisation is then initiated with a few crystals of Form B. Themixture is cooled, stirred for 1 hour at room temperature, then for 2hours at 0° C. The solid which forms is filtered off, washed with 0.6 lof a 6N aqueous hydrochloric acid solution and dried under vacuum at 50°C. (yield: 676 g; 93%).

Analysis for C₂₁H₂₅F₂N₂O₃.2HCl.H₂O: calc. C: 52.41; H: 5.86; N: 5.82;Cl: 14.73; F: 7.89. found C: 52.08; H: 6.03; N: 5.44; Cl: 14.55; F:7.83.

Pseudopolymorphic efletirizine dihydrochloride Forms A and B have beenfurther characterised by their respective X-ray powder diffractionspectra and intrinsic dissolution rates.

I. X-ray powder diffraction spectra.

X-ray powder diffraction spectra were recorded on a PHILIPS PW 1710diffractometer using the CuK_(α) radiation as source. The samples ofpowder to be analyzed were poured into the sample holder withoutgrinding or mixing. The spectra were recorded at room temperature from2θ=4° to 2θ=50° with a scan speed of 1°/min.

For Form A, characteristic diffraction peaks are observed at 2θ valuesof: 13.7°±0.5; 13.9°±0.5; 16.3°±0.5; 18.0°±0.5; 18.6°±0.5; 19.1°±0.5;23.1°±0.5; 24.1°±0.5; 25.6°±0.5; and 30.2°±0.5.

For Form B, characteristic diffraction peaks are observed at 2θ valuesof: 7.5°±0.5; 9.7°±0.5; 10.5°±0.5; 10.7°±0.5; 15.7°±0.5; 18.9°±0.5;19.6°±0.5; 19.9°±0.5; 20.4°±0.5; 20.9°±0.5; 22.2°±0.5; 22.5°±0.5;24.6°±0.5; 24.7°±0.5; 25.9°±0.5; and 29.3°±0.5.

II. Intrinsic dissolution rate.

Drug bioavailability studies have shown that an intrinsic dissolutionrate (IDR) lower than 0.1 mg/cm²/min can often be predictive of adissolution rate-limited absorption in humans. Thus, IDR is a predictiveparameter of bioavailability. This parameter depends upon variousphysicochemical properties including, the chemical form (salt, solvate),the crystal form, the solubility and wettability.

The determination of IDR was performed in the following way. The Form tobe tested was homogeneously ground and mixed with microcrystallinecellulose AVICEL PH102 (dry binder which improves tableting properties).The substance:excipient mix ratio was 70:30 (w/w). Aliquots (500 mg)were compressed into pellets by compression until a final applied loadof 10 tons in order to obtain a constant and known surface area of zeroporosity.

The dissolution experiments were carried out at 37° C. using 500 ml ofaqueous media at three different pH values intended to cover theexpected range of human gastrointestinal pH values, i.e. 1.2, 4.0 and7.5. Uniform and reproducible haemodynamic conditions were obtained bycarrying out the test with USP XXII apparatus N°2 (United StatesPharmacopoeia, 1990) in which a paddle is used as stirring element (50rpm) and the pellet assembly is placed at the bottom of the vessel(static disc method). Statistically assessed (p<0.05) linear portions ofall replicate dissolution curves were selected for subsequent IDRcalculation.

The results are presented in Table 1 which shows the IDRs of Form A andForm B expressed in mg/cm²/min at the three pHs tested

TABLE 1 Intrinsic dissolution rates. Intrinsic dissolution rate(mg/cm²/min) pH Form A Form B 1.2 5.04 ± 0.34 4.05 ± 0.64 4.0 5.43 ±0.32 3.58 ± 0.50 7.5 4.52 ± 0.34 3.31 ± 0.04

The results of Table 1 show that both Form A and Form B have IDRs higherthan 0.1 mg/cm²/min at the three pHs tested. This indicates thatdissolution is probably not the rate-limiting step in the in vivoabsorption process for solid pharmaceutical compositions containingeither Form A or Form B. However, Form B has significantly lower IDRsthat Form A. This means that if the fastest possible dissolution of asolid dosage form is wanted from a therapeutic point of view, Form A isthe preferred crystalline form for use in a solid pharmaceuticalcomposition.

The present invention also concerns pharmaceutical compositionscomprising Form A or Form B in association with suitable pharmaceuticalexcipients therefor. In the case of solid pharmaceutical compositions,it is surprisingly more advantageous to use Form A rather than Form B.We have indeed discovered that solid pharmaceutical compositionscomprising Form A in association with the usual carriers and diluentstherefor, such as sorbitol, exhibit better storage stability than thosecomprising Form B.

This is illustrated in the results of the following study, aimed atexamining the stabilities of the two pseudopolymorphic forms in thepresence of D-sorbitol during storage under stress temperatureconditions, that is, in sealed vials at 40 or 60° C.

In this study, HPLC analysis of several samples was performed: Form A,Form B, D-sorbitol and 1:1 (w/w) mixtures of Form A or Form B withD-sorbitol.

Each sample was homogeneously ground and mixed. Aliquots (500 mg) werecompressed into 13 mm diameter pellets at an applied load of 1 ton whicha usual compression strength for pharmaceutical tablets. Each compactpellet was immediately ground into a fine powder, and an aliquot wasstored in a tightly sealed glass vial at 40 or 60° C. Samples wereanalysed by HPLC after 0, 4, 16 and 24 weeks. p In a first series ofanalyses, HPLC/UV spectra were collected using a Kontron HPLC systemtype 300 fitted with a UV detector. The column used was SupercosilRP_(—ABZ) 250×4.6 mm I.D. 5 μm particle size, and the mobile phase usedconsisted of an acetonitrile/water 25:75 (v/v) mixture, the watercontaining 770 mg/l ammonium acetate. Samples to be analysed weredissolved in acetonitrile/water 25:75 (v/v) at a concentration of 2mg/ml, and 10 μl of these solutions were injected in the HPLC system.

Upon comparing the HPLC spectra obtained for the individual componentsand for the binary mixtures, new peaks detected were consideredindicative of an interaction with D-sorbitol. When present, these newpeaks were quantified and further identified by HPLC/MS analysis, usinga VG Quattro spectrometer coupled onto a Kontron HPLC system.

By HPLC/UV, no modifications of the spectrograms were observed for pureForm A and Form B after storage at 40° or 60° C. for 4, 16 or 24 weeks.Pure D-sorbitol was not detected in HPLC/UV. For the binary mixtures,new peaks appeared in the spectrograms upon comparison with the spectraof pure Form A or Form B. The new peaks were particularly significantfor Form B which had been stored at 60° C.

In HPLC/MS, the new peaks observed for the binary mixtures wereidentified as a sorbitol-efletirizine monoester and dehydrated forms ofa sorbitol-efletirizine monoester. The latter appeared after longerstorage periods than the former.

Table 2 shows the results of quantitative determination ofsorbitol-efletirizine monoester formed in the binary mixtures uponstorage at 40° or 60° C. Relative quantification of monoester wasperformed by HPLC-UV analysis.

TABLE 2 Quantification of sorbitol-efletirizine monoester over time.Relative % area 40° C. 60° C. Time (weeks) Form A Form B Form A Form B 00 0 0.03 0.04 4 0.04 0.13 0.29 0.87 16 0.07 0.16 0.45 2.69 24 0.13 0.230.46 2.95

Table 2 shows that when Form A or Form B is compressed in a pellet withD-sorbitol and stored at 40° or 60° C., a sorbitol-efletirizinemonoester forms in an amount which increases over time. Furthermore itshows that monoester formation is quite low for Form A upon storage at40° and 60° C. and for Form B upon storage at 40° C. However monoesterformation is very significant for Form B upon storage at 60° C.

These results show that Form A of efletirizine dihydrochloride interactsless with hydroxylated excipients, carriers or diluents commonly used insolid pharmaceutical compositions and that it is thus more suitable thanForm B for the preparation of such compositions.

The present invention further relates to a pharmaceutical compositioncomprising Form A or Form B or a mixture of Form A and Form B inassociation with suitable excipients, diluents or carriers thereof.Pharmaceutical compositions of the invention may have various forms.Sustained release formulations are of particular interest, and evenprefered compositions comprise a slow release excipient in combinationwith a cyclodextrine.

An example of a such composition is as follows: 30 mg anhydrous2-[2-[4-[bis(4-fluorophenyl) methyl]-1-piperazinyl]ethoxy]acetic aciddihydrochloride; 14.7 mg Encompress®; 82.3 mg cyclodextrine; 70 mgMethocel® K15MCR; 1 mg Aerosil®200; 2 mg magnesium stearate.

What is claimed is:
 1. Anhydrous2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic aciddihydrochloride the X-ray diffraction pattern of which presents peaks at2θ values of: 13.7°±0.5; 13.9°±0.5; 16.3°±0.5; 18.0°±0.5; 18.6°±0.5;19.1°±0.5; 23.1°±0.5; 24.1°±0.5; 25.6°±0.5; and 30.2°±0.5.
 2. Processfor the preparation of anhydrous2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic aciddihydrochloride according to claim 1, wherein2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic aciddihydrochloride monohydrate is heated under reflux in a solvent. 3.Process according to claim 2, wherein the solvent used is acetone ormethylethylketone.
 4. Pharmaceutical composition comprising anhydrous2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic aciddihydrochloride according to claim 1 in association with suitableexcipients, diluents or carriers thereof.
 5. Pharmaceutical compositionaccording to claim 4, which is a solid pharmaceutical compositioncomprising at least one hydroxylated excipient, carrier or diluent. 6.Pharmaceutical composition according to claim 4, which further comprisesa slow release excipient and a cyclodextrine.
 7. Pharmaceuticalcomposition according to claim 5, which further comprises a slow releaseexcipient and a cyclodextrine.